DiscoveryBioMed, Inc. (DBM) completed recently Phase I SBIR-funded goals, milestones, specific experimental aims and efforts to screen 58,000 synthetic organic small molecules on immortalized and primary differentiated human adipocyte platforms and to validate the high-throughput screening (HTS)-based Drug Discovery output with a Critical Path of bioassays detecting secretion of endogenously produced species of the peptide adipokine, adiponectin. This design yielded 12 hit-to-lead chemical classes that are potent and effective in potentiating the endogenous production and secretion of human low, medium and higher molecular weight (HMW) forms of adiponectin, a beneficial adipokine for normal metabolism and insulin target tissue protection that is lost during the emergence and progression of type 2 diabetes mellitus (T2DM) and obesity. Accordingly, up-regulating endogenous adiponectin expression and secretion within the human body has been proposed as a therapeutic strategy for diabetes and obesity, especially to block secondary injury of other fragile human tissues. The ultimate goal of this proposed Phase II work is to select, profile, focus and optimize through medicinal chemistry DBM's lead and back-up lead chemical classes of higher molecular weight adiponectin secretagogue ligands (HMW-ASLs) to realize potent and effective lead clinical candidate drugs that will block secondary complications of T2DM, obesity and related metabolic diseases in the nearer term and attenuate T2DM and obesity in general as a secondary endeavor. The key ingredient in this program is the use of biologically- and disease-relevant human cellular platforms, primary differentiated human adipocytes, to profile hit-to-lead new chemical entities. This core principle reflects DBM's unique angle, approach and offering to the Drug Discovery space, 'Humanized Drug Discovery'. It is DBM's core belief that a successful de novo drug discovery program must utilize a disease-relevant human cell platform and a disease-relevant targeted and phenotypic endpoint (i.e. human adipocytes secreting human adiponectin). The rationale and potential market impact of this DBM Metabolic Diseases Drug Discovery and Development program are straightforward and enormous. Obesity and obesity-related diseases including T2DM, atherosclerosis, cardiovascular disease, fatty liver disease, and diabetic hyperglycemic injury of the eye, heart, vasculature, kidney and peripheral nerves have reached epidemic proportions in the US and the developed world and exact huge morbidity and cost burdens on global society. An immense unmet clinical need exists for new therapeutic drugs to combat these diseases, especially in Alabama where our company resides in the heart of the Southeastern Diabetes Belt. This market is estimated to be $1 trillion by 2015. Yet, metabolic diseases drug discovery and development is at a near standstill. Hence, there is an 'open window of opportunity' to re-kindle the metabolic disease drug discovery effort. Our NIDDK Phase I SBIR award has allowed DBM to launch this critical program. Phase II project milestones are proposed as follows and will continue the momentum of this SBIR- driven program. Current transitional scientific activity seeks to evaluate and select multiple lead and back-up lead chemical series that are potent and effective HMW-ASLs at the onset of the program. Chemoinformatics analyses progressed 12 out of 18 validated hit chemical classes and subsequent medicinal chemistry analyses have selected 8 out of 12 hit-to-lead chemical classes for entry into Phase 2 SBIR-driven work. A continuing milestone seeks to profile 'best in class' compounds from the 8 hit-to-lead HMW-ASL classes in primary human adipocyte culture platforms from normal, T2DM, and overweight/obese donors and from both subcutaneous and visceral adipose tissue sources. Subsequent milestones involve collaborative work with CROs and academic collaborators/consultants in in vitro and in vivo ADME/PK and MTD safety and toxicity studies in mice, in vivo proof-of-concept studies in animal models of T2DM, obesity and related disorders, medicinal chemistry design optimization and profiling of analogs from, ultimately, 2 lead and 2 back-up lead drug classes to improve potency and/or efficacy of chemical series and re-performance of in vivo proof-of-concept studies in metabolic diseases animal models. This proposed Phase II program scripts full IND-enabling studies so as to select a lead clinical candidate drug and seek partnership with an interested BioPharma.